The main objective of this Phase I SBIR application is to perform the first-in-man studies with a new antibody-drug conjugate (ADC) composed of a humanized antibody (hRS7) to the epithelial glycoprotein-1 antigen (EGP-1, also known as TROP-2) coupled to SN-38, the active topoisomerase I inhibitor from irinotecan. TROP-2 is abundantly expressed in many different types of epithelial cancer, and in some instances, it is present in the more aggressive forms. Preclinical testing of the hRS7 ADC has shown it is effective against a variety of human xenografts at non-toxic doses. As a first-in-man experience, we plan on evaluating its activity in advanced pancreatic cancer, since preclinical data have indicted this agent can be combined safely with a 90Y-labeled anti-pancreatic mucin IgG that is currently completing Phase II testing with encouraging anti-tumor activity. Thus, one of our long-term objectives is to build a comprehensive treatment program for the treatment of pancreatic cancer that will combine radioimmunotherapy with ADC. However, if proven safe in the Phase I study in pancreatic cancer, the hRS7-SN-38 could be tested in other cancers (such as breast, ovarian, prostate, and lung cancers). We have completed manufacturing and preclinical assessment of the hRS7-SN-38 ADC, including immunohistology and monkey toxicology studies that will be used to submit an IND, and had pre-IND discussions with the FDA in terms of protocol development. Thus, the goal of this Phase I application will be to complete a dose-escalation trial to determine the maximum tolerated dose or a biologically active dose of the hRS7 ADC in patients with stage III/IV pancreatic cancer who have failed one prior treatment. We expect ~5 cohorts of patients will be required, starting with a dose acceleration design that allows 1 patient per cohort to be enrolled until we observe Grade 2 toxicity that is directly relatd to the test article, and then to proceed using a standard 3+3 Phase I design until dose-limiting toxicity occurs. Two to three clinical sites will participate in this trial, and therefore accrual should be completed within the first year of finding to assess safety, efficacy and immunogenicity of the ADC. We are hopeful that once these assessments are made, a Phase II SBIR application will be filed so that we can continue to a Simon 2-stage Phase II design at a selected dosing regimen to obtain additional safety and efficacy data, enabling us to determine the activity of this agent alone. PUBLIC HEALTH RELEVANCE: This application seeks to perform first-in-man clinical testing of a new antibody-drug conjugate (ADC) that has promising activity in many types of epithelial cancer at non-toxic doses. This trial will focus on its use in patients with advanced metastatic pancreatic cancer, performing a Phase I dose-escalation trial to determine the maximum tolerated dose or a biologically active dose. The broad specificity of this ADC for many cancers means its successful testing in pancreatic cancer can be applied to these other indications. Additionally, preclinical testing has already shown this agent, when combined with a radiolabeled antibody, can enhance overall response without increasing toxicity, making this a very versatile and promising agent for the management of solid tumors.